ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling
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Min Su1, Jingjia Huang1, Jijia Li1, Xiyuan Qin1, Xiaoning Tang1, Fang Jin1, Shali Chen1, Chuanming Jiang1, Zizheng Zou1, Kunjian Peng1, Mohammed Nuruzzaman1, Jianting Zhang1, Junli Luo1, Suyou Liu2, Zhiyong Luo1
1Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
2Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha 410006, China
Zhiyong Luo, e-mail: firstname.lastname@example.org
Suyou Liu, e-mail: email@example.com
Keywords: angiogenesis, ZLM-7, microtubule, VEGF, VEGFR2
Received: October 21, 2015 Accepted: February 05, 2016 Published: March 08, 2016
Inhibition of angiogenesis is a promising therapeutic strategy against cancer. In this study, we reported that ZLM-7, a combretastain A-4 (CA-4) derivative, exhibited anti-angiogenic activity in vitro and in vivo. In vitro, ZLM-7 induced microtubule cytoskeletal disassembly. It decreased VEGF-induced proliferation, migration, invasion and tube formation in endothelial cells, which are critical steps in angiogenesis. In vivo, ZLM-7 significantly inhibited neovascularization in a chicken chorioallantoic membrane (CAM) model and reduced the microvessel density in tumor tissues of MCF-7 xenograft mouse model. ZLM-7 also displayed comparable antiangiogenic and anti-tumor activities associated with the lead compound CA-4, but exhibited lower toxicity compared with CA-4. The anti-angiogenic effect of ZLM-7 was exerted via blockade of VEGF/VEGFR-2 signaling. ZLM-7 treatment suppressed the expression and secretion of VEGF in endothelial cells and MCF-7 cells under hypoxia. Further, ZLM-7 suppressed the VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling mediators including activated AKT, MEK and ERK in endothelial cells. Overall, these results demonstrate that ZLM-7 exhibits anti-angiogenic activities by impairing endothelial cell function and blocking VEGF/VEGFR-2 signaling, suggesting that ZLM-7 might be a potential angiogenesis inhibitor.
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